1. DEVELOPMENT of NERVOUS SYSTEM

2. CONTENT NEURULATION NEURULATION – NEURAL PLATE – NEURAL GROOVE – NEURAL TUBE NEUROHISTOGENESIS NEUROHISTOGENESIS – Formation of Neurons and Glial Cells from Neuroepithelium – Layers and Plates of the Neural Tube FORMATION OF CNS FORMATION OF CNS – Development of Forebrain Diencephalon Telencephalon (Brain) – Development of Midbrain – Development of Hindbrain (Cerebellum) – Development of Hindbrain (Medulla Oblogata) – Spinal Cord Development DEVELOPMENT OF PNS DEVELOPMENT OF PNS – Neurolemmocytes (Schwan cells) – Afferent Neurons – Postganglionic Visceral Efferents Neurons – Somatic Efferent Neurons and Preganglionic Visceral Efferent Neurons FORMATION OF MENINGES AND VENTRICULER SYSTEM FORMATION OF MENINGES AND VENTRICULER SYSTEM

3. Developmental Stage Main Feature of Developmental Stage InductionProduction of cells that will become nervous tissue ProliferationCell reproduction (mitosis) MigrationLocation of cells in appropriate brain areas DifferentiationDevelopment of neurons into particular type SynaptogenesisFormation of appropriate synaptic connections Selective cell deathElimination of mislocated cells and cells that failed to form the proper synaptic connections Functional validation Strengthening of synapses in use, weakening of unused synapses

4. STAGEDAY SIZE (mm) NEUROECTODERMAL EVENTS VIII (Week III) 16-18 1-1,5Event: Differentiated and Invaginate Neural Plate Structure: Neural Groove developed IX (Week III) 18-201,5-2,5Event: Two Flexure Development (Day 19) Structure: Presumptive Brain Vesicles; Forebrain, Midbrain, Hindbrain X (Week IV) 20 -222 - 3,5Event: Folding of Neural Ectoderm Structure: Neural Tube formed Event: Differentiated Neuromere (Day 21) XI (Week IV) 22 -242,5 -4,5Closure of Cranial Neuropore XII (Week IV) 24 - 263 - 5Closure of Caudal Neuropore

5. Major stages of human CNS development (based on Aicardi 1992)

6. NEURULATION The notochord induces overlaying ectoderm. This ectoderm becomes neuroectoderm and form a neural tube. The following stages of neural tube formation are evident: – Neural plate – Neural groove – Neural tube – Neural Crest forming

7. FORMATION OF NEURAL TUBE

8. DERIVATE of NEURAL TUBE and NEURAL CREST CELLS Neural tube becomes central nervous system (CNS). The cavity of the tube (neural cavity) becomes the ventricular system of the brain and the central canal of the spinal cord. Neural crest cells become those neurons of peripheral nervous system (PNS) that have their cell bodies located in ganglia. They also become neurolemmocytes (Schwann cells) of the PNS. Additionally, neural crest cells become adrenal medulla cells, melanocytes of skin and a variety of structures in the face.

9. NEUROHISTOGENESIS Neuroepithelium gives rise to neurons, glial cells (astrocytes and oligodendrocyte), and ependymal cells. Neuroepithelial cells have processes which contact the inner and outer surfaces of the neural tube.

11. NEURAL TUBE LAYERS Ectodermal cells of the early tube develop 3 concentric zones, – 1) germinal (or matrix); Cells near the central canal are called the germinal layer. Germinal or an internal, columnar ependymal layer becomes the ependymal lining and epithelium of choroid plexus, – 2) mantle layer; a middle, densely packed layer of mantle cells becomes the gray matter of the CNS, – 3) marginal layer; an external marginal layer composed mainly of the processes of cells of the mantle layers becomes the white matter of the CNS.

12. NEURAL CREST DERIVATIVES LEGEND: A: Neural Crest  1a; Bipolar Neuroblast  1b; Bipolar Neuroblast (Differentiation)  1c; Unipolar Spinal Ggl. Neuron  2a; Unipolar Neuroblast  2b; Multipolar Neuron (Sympathic Ggl.)  2c; Medulloblast (Chromaffin Cells)  3a; Glioblast  3b; Schwann cell  3c; Satellite Cell  4a; Mesenchyme cell  4b; Leptomeninx cell (Arachnoid & Pia)  4c; Ectomesenchyme cell  5a; Melanoblast  5b; Melanocyte B: Mantle Zone C: Marginal Zone D: Germinal Zone

13. NEUROHISTOGENESIS; MANTLE LAYER DERIVATIVES LEGEND: A: Neural Crest B: Mantle Zone  7a; Apolar Neuroblast  7b; Bipolar Neuroblast  7c; Unipolar Neuroblast  7d; Mature Neuron  8a; Glioblast  8b Protoplasmic Astrocyte  8c; Fibrillar Astrocyte  8d; Oligodendrocyte C: Marginal Zone D: Germinal Zone

14. NEUROHISTOGENESIS: MARGINAL LAYER DERIVATIVES Additionally, the CNS contains blood vessels and microglial cells derived from mesoderm. LEGEND: A: Neural Crest B: Mantle Zone C: Marginal Zone  9a Mesenchyme cell  9b Microglia D: Germinal Zone

15. NEUROHISTOGENESIS: GERMINAL LAYER DERIVATIVES LEGEND: A: Neural Crest B: Mantle Zone C: Marginal Zone D: Germinal Zone  10; Ependymocyte  11; Choroid Plexus Epithelium  12; Pinealocyte  13; Pituicyte

16. NEURON FORMATION Neurons develop from neuroblasts of the neuroepithelium and migrate into the mantle layer. The neuroblast changes into a bipolar cell. Bipolar cell has a primitive axon and dendrite. The single dendrite degenerates and is replaced by multiple dendrites forming a multipolar neuroblast. Neurons that fail to make viable contacts are destined to degenerate.

17. NEURAL TUBE HISTOGENESIS During week 4, the neural groove closes to form a neural tube beginning in the region of the 4th - 6th somites; Fusion of neural folds proceeds cranially and caudally Thus Neural tube forms the brain and spinal cord respectively. Firstly, neural tubes consist of single columnar cell layer. Then, this layer divides to form a pseudostratified neuroepithelium. So wall of the tube becomes thick and eventually producing neuroblast and glioblast (spongioblast).

18. PATTERN FORMATION OF NEURAL TUBE Subdivision of the neural tube are specified through pattern formation which take place in TWO directions: Dorsoventral; generates Longitudinal Areas: – ALAR ( Roof) PLATES; Sensory, – BASAL (Floor) PLATES; Motor Rostrocaudal; generates Transverse Zones: NEUROMERES.

19. DORSOVENTRAL PATTERN FOMATION of NEURAL TUBE Longitidunal groove of midline regions called the sulcus limitans Sulcus limitans separates the developing gray matter into a dorsal (alar-roof) plate and a ventral (basal-floor) plate.

20. MEDIOLATERAL PATTERN FOMATION of NEURAL TUBE The basal plate contains efferent neurons that send output axons into the PNS. The alar plate contains afferent neurons that receive input from the PNS.

21. ROSROCAUDAL PATTERN FOMATION of NEURAL TUBE Neuromeres are segmentally arranged transverse bulges along the neural tube, particularly evident in the hindbrain. Each neuromere has alar (dorsal) and basal (ventral) components. Neuromeres gradually fade after day 32 (5 Week; stage 15).

22. PRIMARY NEUROMERES Six (6) primary neuromeres appear already at stage 9 (18-20 day, week III) when the neural folds are not fused: – Prosencephalon (T, D1- D2), – Mesomere – Four rhombomere (A–D). LEGEND: T: Telencephalic Neuromere D1-D2: Diencephalic Neuromere M: Mesomere Rh A-D: Rhombomere nch: Notochord mclo: Cloacal Membrane CE: Caudal Eminence Procencephalon

23. SECONDARY NEUROMERES  Sixteen (16) secondary neuromeres can be recognized from about four week.  Six Prosomere (P1-P6) of forebrain  A mesomeres (M) of the midbrain,  An isthmic neuromere (I),  Eight rhombomeres (Rh1–Rh8).

24. DERIVATIVES OF THE PROSOMERES P6: (T) Telencephalic neuromere; Brain Cortex, Medial and Lateral Ganglionic Eminece P5: Optic Vesicle P4 (D1) Diencephalic neuromere; medial ganglionic eminence, hypothalamus various part P3: (D2-P3):The parencephalon rostralis (prospective prethalamus) P2: (D2-P2): The parencephalon caudalis (prospective thalamus). P1: (D2-P1): The synencephalon (prospective pretectum).

25. EARLY DEVELOPMENT OF BRAIN (CNS) Even on day 19 (Begining of Week III); The neural tube becomes bent by two flexures: – (1) the mesencephalic flexure at the midbrain level, already evident before fusion of the neural folds; – (2) the cervical flexure, situated at the junction between the rhombencephalon and the spinal cord,

26. EARLY DEVELOPMENT OF BRAIN (CNS) The three main divisions of the brain can already be recognized when the neural tube is not yet closed. These three part: – Prosencephalon (Forebrain) – Mesencephalon (Midbrain) – Rhombencephalon (Hindbrain)

27. EARLY DEVELOPMENT OF BRAIN (CNS) During the FIFTH WEEK (DAY 32 & Stage 15); Reverse, dorsal flexion (pontine flexure) occurs: Begins at the location of the developing pons Mesencephalon enlarges, The prosencephalon rotates ventrally and then posteriorly around this turning point (hinge) during the fourth and fifth weeks until it is folded back under the mesencephalon. The prosencephalon and rhombencephalon each subdivide into two portion. Converting the three primary brain vesicles into five secondary brain vesicles.

28. EARLY DEVELOPMENT OF BRAIN (CNS) Future cerebral hemispheres can be recognized by day 32 (Early Week V). The forebrain soon divides into an end portion, the telencephalon, and the diencephalon that can be identified because it gives rise to the optic vesicles. The hindbrain into a rostral (cranial) part develop into the metencephalon, – Metencephalon becomes the cerebellum, the pons and the trigeminal nerve The hindbrain into a caudal part becomes the medulla oblongata or myelencephalon. The junction between the hindbrain and midbrain is relatively narrow and is known as the isthmus rhombencephali.

29. FORMATION OF CNS

32. TELENCEPHALONE DEVELOPMENT A thin roof and lateral part, the pallium, that becomes the future cerebral cortex. A thick basal (floor) part, the subpallium, that becomes the future basal ganglia LEGEND: MP: Medial Pallium DP: Dorsal Pallium LP: Lateral Pallium VP: Ventral Pallium dLGE: Dorsal part of Lateral Ganglionic Eminence vLGE: Ventral part of Lateral Ganglionic Eminence MGE: Medial Ganglionic Eminence

33. DEVELOPMENT OF THE CORTEX MP: Medial Pallium DP: Dorsal Pallium LP: Lateral Pallium VP: Ventral Pallium dLGE: Dorsal part of Lateral Ganglionic Eminence vLGE: Ventral part of Lateral Ganglionic Eminence MGE: Medial Ganglionic Eminence AEP/POA: AnteriorEntoPedincular Region / PreOptic Area The pallium is divided into 4 parts (Based on supposed developmental differences):  A medial pallium or archipallium; Developed hippocampal cortex.  A dorsal pallium or neopallium: Developed neocortex of cerebrum  A lateral pallium or paleopallium: Developed olfactory cortex  Recently, an additional ventral pallium was added. Ventral pallium is developed by claustroamygdaloid complex The subpallium consists of three progenitor domains The Lateral Ganglionic Eminences; generate the striatum (Caudate, Putamen and Accumbens), The Caudal Ganglionic Eminences; give rise the Amygdala (part of limbic system). The Medial Ganglionic Eminences (part of diencephalone), generate the globus pallidus.

34. DEVELOPMENT OF THE CORTEX Red: Archeocortex Blue: Paleocortex

36. 4 Month Arrow: Central Sulcus 6 Month 8 Month Neonate

37. FETAL DEVELOPMENT OF THE BRAIN During the fetal period, the complex pattern of sulci and gyri arises. On the lateral surface of the brain the sulcus lateralis and the sulcus centralis can be recognized from 4 months (16 week) onwards.

38. FETAL DEVELOPMENT OF THE BRAIN Owing to the development of the prefrontal cortex, the sulcus centralis gradually moves caudalwards. On its medial surface first the parieto-occipital and cingulate sulci appear, Followed by the calcarine and central sulci. The plexus choroideus of the lateral ventricle arises in the lower part of the medial wall of the telencephalic vesicle.

39. CLASSIFICATION OF THE CORTEX Based on the differences in lamination the cerebral cortex can be classified into two major groups: – Isocortex (homotypical cortex), the part of the cortex with six layers – Allocortex (heterotypical cortex) with variable number of layers, such as; olfactory cortex and hippocampus.

40. CORTEX CYTOARCHITECTURE The developing cerebral wall contains several transient embryonic zones: 1.The ventricular zone is composed of dividing neural progenitor cells; 2.The subventricular zone (SVZ), which acts early in corticogenesis as a secondary neuronal progenitor compartment and later in development as the major source of glial cells; 3.The intermediate zone (IZ), through which migrating neurons traverse along radial glial processes;

41. CORTEX CYTOARCHITECTURE 4.The subplate, thought to be essential in orchestrating thalamocortical connectivity and pioneering corticofugal projections, 5.The cortical plate, the initial condensation of postmitotic neurons that will become layers II–VI of the mature cortex; 6.The marginal zone (MZ), the superficial, cell-sparse layer that is important in the establishment of the laminar organization of the cortex.

42. CORTEX CYTOARCHITECTURE Most pyramidal cells in the cornu Ammonis fields are generated in the first half of pregnancy (24th gestational week). Granule cells of the dentate gyrus proliferate at a decreasing rate during the second half of pregnancy After birth but still occur proliferation of granule cells at a low percentage during the first postnatal year.

43. DIENCEPHALON DEVELOPMENT Diencephalic Neuromeres: Neuromere D1 (P4) gives rise to – The Medial Ganglionic Eminences (Globus Pallidus), – Various part of Hypothalamus The diencephalic neuromere D2 (Prosomeres P 1-3) can be further subdivided into – The synencephalon (P1) (prospective pretectum), – The parencephalon caudalis (P2) (prospective thalamus), – The parencephalon rostralis (P3). (prospective prethalamus).

45. DIENCEPHALON DEVELOPMENT The alar component of the synencephalon forms the pretectum, The caudal parencephalon (alar component) forms the dorsal thalamus and epithalamus, The rostral parencephalon (alar component) forms the ventral thalamus. The basal components jointly form the prerubral tegmentum.

46. THALAMUS DEVELOPMENT ET: Epithalamus; DT: Dorsal Thalamus VT: Ventral Thalamus TE: Thalamic Eminence HT: Hypothalamus Str: Striatum DG: Dentate Gyrus Hp: Hippocampus LV: Lateral Ventricle VP: Ventral Pallium The thalamus acts primarily as the relay center for the cerebral cortex. It receives all the information (sensory and other) projecting to the cortex from subcortical structures. All information processes thalamus. If it can necessary, appropriate cortical area's communicates.. The Thalamus includes: – The sense of sight (vision) is handled by the lateral geniculate body – The sense of hearing by the medial geniculate body.

47. HYPOTHALAMUS DEVELOPMENT The hypothalamus regulates the endocrine activity of the pituitary as well as many autonomic responses. It participates in the limbic system, which controls emotion and coordinates emotional state with the appropriate visceral responses. The hypothalamus also controls the level of arousal of the brain (sleep and waking). The small epithalamus gives rise to a few miscellaneous structures.

48. MESENCEPHALON DEVELOPMENT The Mesencephalon is primarily a relay (communicate) center. Midbrain also contain cranial nerve nuclei, visual and auditory centers and other structures. Much of the mesencephalon is composed of white matter, Principally the massive tracts connect the forebrain with the hindbrain and spinal cord.

49. MESENCEPHALON DEVELOPMENT FOUR CRANIAL NERVE NUCLEI The midbrain also contains a number of important neuronal centers, including four cranial nerve nuclei. – The motor nuclei of the oculomotor (III) – The general visceral efferent (Edinger-Westphal) nucleus – The motor nuclei of the trochlear (IV) nuclei – A portion of the sensory nucleus of the trigeminal nerve (V) called the mesencephalic trigeminal nucleus The trochlear and mesencephalic trigeminal nuclei originate in the metencephalon and are secondarily displaced into the mesencephalon.

50. MESENCEPHALON DEVELOPMENT FOUR CRANIAL NERVE NUCLEI Only the two serving the oculomotor nerve arise from mesencephalic neuroblast; The somatic motor oculomotor nucleus controls the movements of all but the superior oblique and lateral rectus extrinsic ocular muscles, The Edinger-Westphal nucleus supplies parasympathetic pathways to the pupillary constrictor and the ciliary muscles of the eye globe.

51. MESENCEPHALON DEVELOPMENT SUPERIOR AND INFERIOR COLLICULI DEVELOPMENT The superior and inferior colliculi are visible as four prominent swellings on the dorsal surface of the midbrain. The colliculi are formed by mesencephalic alar plate cells that proliferate and migrate medially into the roof plate. The roof plate thickening produced by these cells is subsequently divided by a midline groove into a pair of lateral corpora bigemina.

52. MESENCEPHALON DEVELOPMENT SUPERIOR AND INFERIOR COLLICULI DEVELOPMENT They are later subdivided into inferior and superior colliculi by a transverse groove. The superior colliculi receive fibers from the retinas and mediate ocular reflexes. The inferior colliculi, in contrast, form part of the perceptual pathway by which information from the cochlea is relayed to the auditory areas of the cerebral hemispheres.

53. MESENCEPHALON DEVELOPMENT CEREBRAL AQUEDUCT During development, the primitive ventricle of the mesencephalon becomes the narrow cerebral aqueduct. The cerebrospinal fluid normally flows through the cerebral aqueduct to reach the fourth ventricle. However, various conditions can cause the aqueduct to become blocked during fetal life. Obstruction of the flow of cerebrospinal fluid through the aqueduct results in the congenital condition called hydrocephalus, As a result the third and lateral ventricles are swollen with fluid. The cerebral cortex is abnormally thin, and the sutures of the skull are forced apart.

54. METENCEPHALON DEVELOPMENT The metencephalon gives rise to two structures: – The pons, which functions mainly to relay signals between the spinal cord and the cerebral and cerebellar cortices, – The cerebellum, which is a center for balance and postural control. CEREBELLUM PONS APBP

55. PONS DEVELOPMENT The Pons Is Composed Largely of White Matter Tracts That Serve the Cerebellum The pons (named after the Latin word for bridge) consists mainly of massive fiber tracts that relay information between the cerebrum, the cerebellum, and the spinal cord. These tracts arise primarily from the marginal layer of the basal columns of the metencephalon In addition, ventrally located pontine nuclei relay input from the cerebrum to the cerebellum.

56. PONS DEVELOPMENT The pons consists of 2 parts: – a) The phylogenetically older dorsal portion called the pontine tegmentum Pontine tegmentum lies in the floor of the 4th ventricle This is continuous with the medulla This area exhibits a similar organization to medulla – b) The phylogenetically newer; basis pontis which develops later. Pontine nuclei in the basis pontis upon which corticofugal fibers terminate.

57. PONS DEVELOPMENT Pons consist of two plates; Alar and Basal These plates includes afferent and efferent nuclei, This plates lie medial and lateral to the sulcus limitans, respectively.

58. PONS DEVELOPMENT Alar plates move laterally and the cavity of the neural tube expands dorsally forming a Fourth ventricle. The basal plate (containing efferent neurons of cranial nerves) is positioned medial to the alar plate and ventral to the fourth ventricle; White and Gray matter (marginal & mantle layers) become intermixed (unlike spinal cord);

59. PONS DEVELOPMENT The roof of the fourth ventricle (roof plate) is stretched and reduced to a layer of ependymal cells covered by pia mater; A choroid plexus develops bilaterally in the roof of the ventricle and secretes cerebrospinal fluid;

60. PONS COMPONENT Basal Plate components: – GSE (General Somatic Efferent), Abducens nucleus of CN VI – SVE (SomatoVisceral Efferent), motor components to muscle of branchiomeric origin of CNs V and VII – GVE (General Visceral Efferent), superior salivatory nucleus of CN VII

61. PONS COMPONENT Alar Plate components: – SSA (Special Somatic Afferent), vestibulocochlear components of CN VIII – GSA (General Somatic Afferent), trigeminal sensory for pain & temperature, CN V – SVA (Special Visceral Afferent) & GVA (General Visceral Afferent), solitary nucleus for taste & visceral sensation of CNs VII, IX, X

63. CEREBELLUM DEVELOPMENT The cerebellum is derived largely from the rhombic lips of the metencephalon. It begins to develop at the end of the sixth week. It continues to grow after birth. 1.The metencephalic rhombic lips thicken at the end of the sixth week to produce a pair of cerebellar plates (cerebellar primordia). 2.By the second month, the cranial portions of the growing rhombic lips meet across the midline, Thus, single primordium is formed. 3.By the middle of the third month, the growing cerebellum begins to grow dorsally.

64. CEREBELLUM DEVELOPMENT 4.At the middle of the third month the developing cerebellum is occured transverse groove. Transverse groove is called the posterolateral fissure. Posterolateral fissure separetes developing cerebellum into cranial and caudal portions. The caudal portion, consisting of a pair of flocculonodular lobes (primitive part). The larger cranial portion consists of a narrow median swelling This is called the vermis. 5.The cerebellar vermis and hemispheres undergo an convoluted process.

65. CEREBELLAR CYTOARCHITECTURE The cerebellum has two types of gray matter: A group of internal deep cerebellar nuclei An external cerebellar cortex. Four deep nuclei form on each side: – The dentate, – The globose, – The emboliform, – The fastigial nuclei. All the input to the cerebellar cortex is relayed through these nuclei.

66. CEREBELLAR CYTOARCHITECTURE In the third month, a second layer of proliferating cells appears in the most superficial layer of the marginal zone. The ventricular proliferating layer is now called the internal germinal layer, The new layer is called the external germinal layer (or, sometimes, the external granular layer).

67. MYELENCEPHALON DEVELOPMENT Neuroblasts of the brainstem develop in a similar to the spinal cord. Alar and basal plates of the medulla form motor and sensory columns of cells that supply cranial nerves. The organization of alar and basal plates differ from of the spinal cord: 1) in the medulla and pons the alar plate lies lateral to the basal plate, (not dorsal to) – The 4th ventricle is “open”, 2) There are migrations of neuroblasts of both plates from the ventricular floor to other locations, 3) “special” sensory and motor structures of the head require new/different cell groups for innervations.

68. MYELENCEPHALON DEVELOPMENT Brainstem development from the medulla through the midbrain resembles that of the spinal cord (i.e., gray matter is derived from alar and basal plates). Rostral to the midbrain i.e., diencephalon and cerebral hemispheres develop from the alar plate. The cerebellum also develops from alar plate.

69. SPINAL CORD DEVELOPMENT The neural cavity becomes central canal lined by ependymal cells; As the spinal cord develops neuroblasts of the neural tube’s mantle layer proliferate in second zones. In cross section the mantle layer develops a characteristic “butterfly”-shape of gray matter. The lateral walls of the tube thicken but leave a shallow.

71. SPINAL CORD DEVELOPMENT Longitidunal groove called the sulcus limitans which separates the developing gray matter into a dorsal alar plate and a ventral basal plate.

72. SPINAL CORD DEVELOPMENT Growth of alar and basal plates, but not roof and floor plates, results in symmetrical right and left halves separated by a ventral median fissure and a dorsal median fissure (or septum).

73. ALAR PLATE Alar plate: Neuronal cell bodies here form nuclei which constitute the uninterrupted dorsal gray matter (or columns) that receive and relay input from afferent (sensory, somatic and visceral) neurons. – It extends the length of the cord. – These neurons receive sensory information from axons in the dorsal roots of spinal nerves.

74. BASAL PLATE Basal plate: Cell bodies here form the uninterrupted ventral gray matter (or columns) of efferent neurons.

75. SPINAL CORD DEVELOPMENT The mantle layer develops into gray matter, i.e., dorsal and ventral gray columns separated by intermediate gray matter (in profile, the columns are usually called horns); Cell migration from the basal plate produces a lateral gray column (horn) at thoracic and cranial lumbar levels of the spinal cord (sympathetic preganglionic neurons); The marginal layer becomes white matter (which is subdivided bilaterally into a dorsal funiculus (bundle), a lateral funiculus, and a ventral funiculus )

76. The marginal layer increases in mass due to the addition of longitudinally running intersegmental axons, Long ascending axons from the gray matter, Long descending axons from supraspinal levels and incoming dorsal root sensory fibers. The mass of fibers in the marginal layer subsequently becomes myelinated (beginning in the 4th month) and is called white matter.